HLA-A*02:01-restricted PR1-specific T-cell receptor (PR1-TCR) (PR1-TCR)

The PR1-specific T-cell receptor (TCR) is a specialized immune receptor found on CD8+ cytotoxic T lymphocytes that recognizes the PR1 peptide presented by the HLA-A*02:01 molecule. PR1 is a nonameric peptide (VLQELNVTV) derived from the myeloid-associated proteins Proteinase 3 and Neutrophil Elastase, which are significantly overexpressed in the granules of myeloid leukemia cells, such as those in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) (Molldrem et al., 2000, Nature Medicine). Upon binding to the HLA-A2:PR1 complex, the TCR triggers a signaling cascade that leads to the activation of the T cell and the subsequent release of perforins and granzymes to induce apoptosis in the target leukemia cell (Rezvani et al., 2007, Blood). This TCR is a major focus in cancer immunotherapy, serving as the basis for PR1 peptide vaccines and the development of TCR-engineered T-cell (TCR-T) therapies (Alatrash et al., 2017, Journal of Immunotherapy). While highly effective at targeting malignant cells, therapeutic strategies must manage the risk of on-target, off-tumor toxicity, as the PR1 peptide is also presented by normal hematopoietic progenitor cells and mature neutrophils (Ma et al., 2016, Cancer Research). The specificity of this TCR for the HLA-A2:PR1 complex allows for the selective elimination of leukemia-initiating cells while sparing most non-myeloid tissues. Clinical monitoring of PR1-specific T-cell frequencies has shown that their presence correlates with clinical remission and the graft-versus-leukemia effect after stem cell transplantation. Ongoing research aims to optimize the affinity of these TCRs to enhance anti-tumor efficacy without increasing toxicity to healthy bone marrow.

Other names

PR1-specific T-cell receptorHLA-A2/PR1-specific TCRProteinase 3/Neutrophil Elastase-derived peptide-specific TCRPR1-CTL receptorPR1-specific CD8+ T-cell receptor

The TCR recognizes the PR1 peptide (VLQELNVTV) presented by HLA-A*02:01 on the surface of myeloid leukemia cells, triggering T-cell activation, cytokine production, and directed lysis of the target cell via the release of cytotoxic granules.